From the Population Health Research Institute (S.J.C., J.W.E., D.M.S., E.Z., B.M., S.A., J.N.) and the Department of Medicine (M. Crowther), McMaster University, Hamilton, ON, and the University of Calgary, Calgary, AB (A.M.D.) - all in Canada; Harvard Medical School (C.M.G.) and Brigham and Women's Hospital (D.J.P.) - both in Boston; Portola Pharmaceuticals, South San Francisco, CA (J.T.C., J.H.L., P.Y., M.D.B., G.L., P.B.C., S.G., J.L., S.S.); University of Leuven, Leuven, Belgium (P.V.); Centre Hospitalier Universitaire de Clermont-Ferrand, Clermont-Ferrand (J.S.), and Grenoble-Alpes University Hospital, Grenoble (P.A.) - both in France; Academic Medical Center, Amsterdam (S.M.); Guy's and St. Thomas' Hospitals, King's College London, London (A.T.C.); University Hospital Carl Gustav Carus Dresden, Dresden, Germany (J.B.-W.); Instituto de Investigación Hospital Universitario La Paz, Madrid (J.L.-S.); Sarasota Memorial Hospital, Sarasota, FL (M. Concha); and Seton Dell Medical School Stroke Institute, Austin, TX (T.J.M.).
N Engl J Med. 2019 Apr 4;380(14):1326-1335. doi: 10.1056/NEJMoa1814051. Epub 2019 Feb 7.
Andexanet alfa is a modified recombinant inactive form of human factor Xa developed for reversal of factor Xa inhibitors.
We evaluated 352 patients who had acute major bleeding within 18 hours after administration of a factor Xa inhibitor. The patients received a bolus of andexanet, followed by a 2-hour infusion. The coprimary outcomes were the percent change in anti-factor Xa activity after andexanet treatment and the percentage of patients with excellent or good hemostatic efficacy at 12 hours after the end of the infusion, with hemostatic efficacy adjudicated on the basis of prespecified criteria. Efficacy was assessed in the subgroup of patients with confirmed major bleeding and baseline anti-factor Xa activity of at least 75 ng per milliliter (or ≥0.25 IU per milliliter for those receiving enoxaparin).
Patients had a mean age of 77 years, and most had substantial cardiovascular disease. Bleeding was predominantly intracranial (in 227 patients [64%]) or gastrointestinal (in 90 patients [26%]). In patients who had received apixaban, the median anti-factor Xa activity decreased from 149.7 ng per milliliter at baseline to 11.1 ng per milliliter after the andexanet bolus (92% reduction; 95% confidence interval [CI], 91 to 93); in patients who had received rivaroxaban, the median value decreased from 211.8 ng per milliliter to 14.2 ng per milliliter (92% reduction; 95% CI, 88 to 94). Excellent or good hemostasis occurred in 204 of 249 patients (82%) who could be evaluated. Within 30 days, death occurred in 49 patients (14%) and a thrombotic event in 34 (10%). Reduction in anti-factor Xa activity was not predictive of hemostatic efficacy overall but was modestly predictive in patients with intracranial hemorrhage.
In patients with acute major bleeding associated with the use of a factor Xa inhibitor, treatment with andexanet markedly reduced anti-factor Xa activity, and 82% of patients had excellent or good hemostatic efficacy at 12 hours, as adjudicated according to prespecified criteria. (Funded by Portola Pharmaceuticals; ANNEXA-4 ClinicalTrials.gov number, NCT02329327.).
Andexanet alfa 是一种改良的重组失活人因子 Xa，用于逆转因子 Xa 抑制剂。
我们评估了 352 名在因子 Xa 抑制剂给药后 18 小时内发生急性大出血的患者。患者接受 andexanet 推注，随后进行 2 小时输注。主要转归是 andexanet 治疗后抗因子 Xa 活性的百分比变化和输注结束后 12 小时内止血效果极佳或良好的患者百分比，根据预设标准判断止血效果。在基线抗因子 Xa 活性至少为 75ng/ml（或接受依诺肝素的患者为≥0.25IU/ml）且确认有大出血的患者亚组中评估疗效。
患者平均年龄为 77 岁，大多数有严重的心血管疾病。出血主要为颅内（227 例[64%]）或胃肠道（90 例[26%]）。接受阿哌沙班治疗的患者，基线时抗因子 Xa 活性中位数从 149.7ng/ml 降至 andexanet 推注后的 11.1ng/ml（92%降低；95%置信区间[CI]，91 至 93）；接受利伐沙班治疗的患者，中位数从 211.8ng/ml 降至 14.2ng/ml（92%降低；95%CI，88 至 94）。249 例可评估患者中有 204 例（82%）止血效果极佳或良好。30 天内，49 例患者（14%）死亡，34 例患者（10%）发生血栓事件。抗因子 Xa 活性降低与总体止血效果无关，但在颅内出血患者中具有适度的预测性。
在与因子 Xa 抑制剂使用相关的急性大出血患者中，andexanet 治疗可显著降低抗因子 Xa 活性，根据预设标准判断，12 小时时 82%的患者止血效果极佳或良好。（由 Portola 制药公司资助；ANNEXA-4 ClinicalTrials.gov 编号，NCT02329327）。
